15
Statistical, pathophysiological and clinical aspects of the relationship
between multiple sclerosis and osteoporosis
Statystyczne, patofizjologiczne i kliniczne aspekty związku między stwardnieniem rozsianym
i osteoporozą
1 Chair of Neurology, Poznan University of Medical Sciences, Poznan, Poland
2 Department of Clinical Neuroimmunology, Chair of Neurology, Poznan University of Medical Sciences, Poznan, Poland 3 Neuroimmunological Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Poznan, Poland
Correspondence: Tomasz Grzegorski, MD, ul. Przybyszewskiego 49, 60-355 Poznań, tel.: +48 663 467 664; e-mail: tomgrzeg@wp.pl
Recently there has been a large increase in a number of publications regarding bone health in multiple sclerosis as well as studies exploring the possible role of vitamin D in the aetiology of the condition. However, the relationship between multiple sclerosis and osteoporosis remains not widely discussed among clinicians. The aim of our review article is to present crucial aspects of such relationship as well as therapeutic options. There are many statistical facts suggesting that correlation between two said diseases occurs. The prevalence of osteoporosis clinical features, like pathological fractures, decreased bone mineral density or low vitamin D serum level, is greater in patients with multiple sclerosis. These facts can be explained by a wide variety of areas and pathways which are common for multiple sclerosis and osteoporosis. The functions of different mediators involved in the pathophysiology of diseases, the role of vitamin D and the adverse effects of drugs administered in multiple sclerosis serve as the best examples. Unfortunately, no uniform guidelines on the management of multiple sclerosis patients with osteoporosis have been established so far. However, the guidelines of the United Kingdom National Institute for Health and Care Excellence and National Osteoporosis Society are recommended in such cases. The most important are an appropriate vitamin D and calcium supplementation, smoking cessation, alcohol intake reduction and more of physical activity. There is a strong need to spread this knowledge among clinicians. A better understanding of the topic might result in the creation of diagnostic and therapeutic guidelines with this respect.
Key words: multiple sclerosis, osteoporosis, bone health, fractures, vitamin D
W ostatnim czasie znacznie wzrosła liczba publikacji dotyczących stanu zdrowia kości w stwardnieniu rozsianym, jak również możliwej roli witaminy D w etiologii wspomnianej jednostki chorobowej. Jednakże związek między stwardnieniem rozsianym i osteoporozą w dalszym ciągu nie jest szeroko omawiany wśród klinicystów. Celem naszego artykułu poglądowego jest przedstawienie kluczowych aspektów wspomnianej korelacji oraz opcji terapeutycznych. Wiele faktów z zakresu statystyki przemawia za tym, że związek między omawianymi dwoma chorobami występuje. Rozpowszechnienie cech charakterystycznych dla obrazu klinicznego osteoporozy, takich jak złamania patologiczne, zmniejszenie mineralnej gęstości kości oraz niskie stężenie witaminy D w surowicy, jest większe wśród chorych na stwardnienie rozsiane. Może to być wyjaśnione licznymi, wspólnymi dla stwardnienia rozsianego i osteoporozy, obszarami i ścieżkami patofizjologicznymi. Ich przykładem są funkcje różnych mediatorów odgrywających rolę w patogenezie obu chorób, rola witaminy D oraz działania niepożądane leków stosowanych w terapii stwardnienia rozsianego. Niestety, do tej pory nie powstały uniwersalne wytyczne dotyczące postępowania w sytuacji współwystępowania stwardnienia rozsianego i osteoporozy. W takich przypadkach rekomendowane są wytyczne Narodowego Instytutu Zdrowia i Klinicznej Doskonałości Zjednoczonego Królestwa oraz Narodowego Towarzystwa Osteoporozy. Największe znaczenie mają odpowiednia suplementacja witaminy D i wapnia, zaprzestanie palenia, zmniejszenie spożycia alkoholu i zwiększenie aktywności fizycznej. Istnieje silna potrzeba rozpowszechnienia znajomości tego zagadnienia wśród klinicystów. Lepsze jego rozumienie może doprowadzić do stworzenia wytycznych uwzględniających aspekty diagnostyczne i terapeutyczne.
Słowa kluczowe: stwardnienie rozsiane, osteoporoza, zdrowie kości, złamania, witamina D
Abstract
Streszczenie
Tomasz Grzegorski
1, Jacek Losy
2,3Received: 20.01.2016 Accepted: 16.03.2016 Published: 31.03.2016
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INTRODUCTION
M
ultiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) associated with the processes of inflammation and demyelation which remains not fully understood. Initially, the in-flammation is usually transient and remyelination occurs, but over time the pathological changes become dominated by a widespread microglial activation connected with an extensive and chronic neurodegeneration. Multiple scle-rosis is the main cause of non-traumatic neurological dis-ability affecting young European adults and their descen-dants (Hollenbach and Oksenberg, 2015).Osteoporosis is a common metabolic bone disease based on a decreased mineral density and microarchitectural distur-bances of the bone tissue. The imbalance between bone re-sorption and formation is a crucial pathophysiological fac-tor in osteoporosis. It leads to an increased risk of fracture, which results in large-scale morbidity particularly among postmenopausal women (Wolski et al., 2015).
Therefore, both multiple sclerosis and osteoporosis are sig-nificant and still growing social problems. What is more, the relationship between them has been noticed. As a re-sult, there has been an increasing publication rate regard-ing bone health in MS in the last 10 years, as well as a large number of studies exploring the possible role of vitamin D in the aetiology of the condition. However, this topic is still not widely known and discussed among clinicians. The aim of this review article is to present crucial aspects of the relationship between MS and osteoporosis as well as therapeutic options. A better understanding of the top-ic might result in the establishment of diagnosttop-ic and ther-apeutic guidelines and will definitely increase the alertness of clinicians, which highlights its scientific and clinical sig-nificance.
CLINICALLY RELEVANT
STATISTICAL DATA
The relationship between MS and osteoporosis seems to have a strong influence on statistical facts connected with these diseases.
First of all, many authors have noticed that the prevalence of fractures in patients with MS is greater than in con-trol groups and proved such correlation. According to the study conducted by North American Research Commit-tee on Multiple Sclerosis (NARCOMS), 15% of subjects suffering from MS had a history of fracture after the age of 13. Among those reporting fractures, 46.2% reported multiple fractures (Marrie et al., 2009). In a case-control study performed in 1998, authors documented a self-re-ported fracture rate in the absence of major trauma oc-curring above the age of 35 years in 22% of 54 patients with MS with a mean Expanded Disability Status Scale (EDSS) result of 6.2 compared to only 2% of 49 healthy controls (Cosman et al., 1998).
Secondly, the structure of the bone tissue is changed in MS patients, which can be easily assessed using bone min-eral density (BMD) and total body bone minmin-eral (TBBM) content parameters. In 2010, Hearn and Silber conducted a cumulative meta-analysis in which they compared sev-eral studies assessing BMD or TBBM in healthy controls and in MS patients. The meta-analysis undoubtedly shows that MS is associated with lower values of BMD as well as TBBM (Hearn and Silber, 2010). In addition, the study per-formed by Weinstock-Guttman et al. (2004) showed that 80% of male MS patients were osteopenic or osteoporotic. These findings can explain more frequent fractures in MS patients compared to the general population.
Furthermore, the level of vitamin D is often investigated in MS patients. Vitamin D plays a key role in bone structure and calcium level maintenance. Its deficit is an essential os-teoporosis risk factor while its adequate intake can delay or prevent osteoporosis (Ishimi, 2015). Polachini et al. (2016) have recently indicated significantly decreased serum levels of vitamin D in MS patients in relation to healthy individu-als. According to the review article by Gibson and Summers (2011), serum 25-hydroxyvitamin D (25-OHD) insufficiency or deficiency in people with MS ranges from 17% to 86.7%, but five of the nine case-control studies have found no statis-tically significant difference in the serum 25-OHD levels be-tween people with MS and healthy controls. Although these results are not consistent, they allow to assume that MS pa-tients might be at high risk of osteoporosis.
Lastly, many authors have been mentioning the correla-tion between MS or its relapses occurrence and the latitude of the place of residence. According to Niino et al. (2014), MS shows a multifold increase in the prevalence with an increase in latitudes, both north and south of the equator. One of the potential factors related to the difference of the prevalence might be vitamin D, because the strength of am-bient ultraviolet light which is essential for vitamin D pro-duction decreases as latitude increases. However, the rela-tionship between MS, the latitude of residence, vitamin D and osteoporosis remains unclear.
MULTIPLE SCLEROSIS
AND OSTEOPOROSIS – COMMON AREAS
AND PATHWAYS
In this paragraph, we attempt to present the most significant reasons for statistical facts mentioned in the previous one as well as to show correlations between them. Generally, there are many common areas in the field of pathophysiology, risk factors and treatment of MS and osteoporosis. Certainly, it contributes to the relationship mentioned in our article.
Cytokines and other mediators
Humoral mediators play a key role in the pathogenesis of either MS or osteoporosis. For instance, proinflammato-ry cytokines like interleukin (IL) 1, tumour necrosis factor
17
(TNF)-α, IL-6, and IL-11 are known to be released fromT helper (Th) as well as other cells and being an impor-tant factor contributing to immunological disturbances in MS (Gupta et al., 2014). On the other hand, these cytokines have been shown to promote osteoclastogenesis. It is essen-tial in the osteoporosis pathogenesis due to the effect on bone loss (via the expression of nuclear factor κB ligand – RANKL) (McLean, 2009).
Moreover, levels of osteopontin were found to be increased in the cerebrospinal fluid of MS patients and shown to be positively correlated with bone density of the femur neck (Gupta et al., 2014). These findings suggest that osteopon-tin is involved in a pathway common to the development of both MS and osteoporosis.
Furthermore, there are many neuronal factors released from CNS cells which, according to a number of studies, might play a role in the pathogenesis of both MS and osteoporosis. Examples of such neuromediators are leptin, neuromedin U and neuropeptide Y. Because of contrary and often con-troversial conclusions of different studies, their detailed role in MS and osteoporosis still remains undiscovered.
Vitamin D
The relationship between MS, osteoporosis and vitamin D is sophisticated and controversial. The role of vitamin D in MS has been investigated both from the point of view of bone health and to explore a possible link to the aetiology of the condition and the occurrence of relapses of MS. Surprisingly, there seems to be no correlation between vitamin D levels and BMD in MS. In 2012, Triantafyl-lou et al. documented the lack of correlation between vi-tamin D levels and decreased BMD at the femoral neck and the lumbar spine in the relapsing-remitting MS pa-tients and stated that vitamin D insufficiency appeared not to be the underlying cause of secondary osteoporo-sis in MS. In 2004, a study was carried out which showed that only 37.5% of MS patients with low BMD had de-creased vitamin D serum levels (Weinstock-Guttman
et al., 2004). The reason for such astonishing findings
may be explained by vitamin D receptor gene polymor-phisms. According to the study performed by Lambrinou-daki et al. (2013), vitamin D receptor’s Bsm1 polymor-phism is associated with a mild effect on BMD in younger patients with MS. However, larger studies are necessary to corroborate these findings.
As mentioned above, the correlation between vitamin D levels and MS can also be investigated in the aspect of vi-tamin D influence on the pathogenesis of MS, disabili-ty status as well as the occurrence of relapses in MS pa-tients. One Australian case-control study found a strong negative correlation between the degree of disability, mea-sured by EDSS, and serum 25-OHD levels (van der Mei
et al., 2007). In addition, it has been indicated that there is
an association between a low vitamin D status at the start of the relapsing-remitting MS and the early conversion to
secondary progressive MS (Muris et al., 2015). These re-sults suggest that vitamin D has a protective effect against pathogenic factors in MS. Many authors have been trying to explain these relations. Findings of the study conduct-ed by Gu et al. (2015) conclude that lesion-associatconduct-ed apop-totic signals in the CNS are reduced following the admin-istration of vitamin D. The results of a study conducted in 2000 suggest that CD8 lymphocytes may be a major site of 1,25-dihydroxyvitamin D3 action, while B lymphocytes might not directly be regulated by 1, 25-dihydroxyvitamin D3 (Veldman et al., 2000). These conclusions highlight an important role of vitamin D in neuroimmunology.
Drugs
Glucocorticosteroids (GCS)
Glucocorticosteroids are basic and the most important drugs used in the treatment of relapses of MS due to their anti-inflammatory effect. On the other hand, adverse re-actions of GCS connected with the bone tissue and the tendency to develop osteoporosis are well known. Meth-ylprednisolone administered intravenously profoundly suppresses bone formation and increases bone resorption (Gibson and Summers, 2011). In fact, the results of stud-ies are quite astonishing. According to them, fractures in MS patients are rather caused by other factors than a ste-roid therapy, like for example impaired gait. The study by Zorzon et al. (2005) showed that repeated pulses of meth-ylprednisolone do not result in a substantially increased risk of osteoporosis in MS patients. In the meta-analysis conducted by Gibson and Summers (2011), in patient ex-posed to pulsed steroids over an average period of approxi-mately 11 years, there is no significant correlation between cumulative steroid dose and the lumbar spine, the femoral neck or total body BMD. It seems likely that intermittent corticosteroid administration has a lesser effect on bones than a continuous therapy. Nonetheless, clinical alertness is necessary because harmful effects of steroid therapy on bone health in MS patients have also been documented (Dovio et al., 2004).
Disease-modifying drugs
These drugs are used to slow the progression of the dis-ease. Among them interferons are the most widely used. Unfortunately, the results and conclusions of studies in-vestigating their potential role in osteoclastogenesis are contradictory.
There is still not enough data on the relation between glat-iramer acetate and the risk of osteoporosis to make scien-tific conclusions.
Interestingly, several studies on the fingolimod (sphingo-sine-1-phosphate) influence on BMD have been performed. In 2009, Ishii et al. published an article in “Nature” jour-nal in which they stated that sphingosine-1-phosphate con-trolled the migratory behaviour of osteoclast precursors, dynamically regulating bone mineral homeostasis in mice.
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Anticonvulsants
Patients with MS have a threefold increase in the risk to develop epilepsy. Anti-epileptic drugs are known to be harmful for bone health. As a result, chronic anticonvul-sant treatment reduces bone strength and increases the risk to develop osteoporosis in MS patients.
Other factors affecting bone health in MS
Cognitive impairment occurs in 40–70% of patients with MS (Guenter et al., 2015). In 2012, Batista et al. conducted a retrospective study in which they documented the asso-ciation between a reduced BMD in patients suffering from MS and the cognitive deficit. An explanation of this result can be found in an increasing number of studies suggest-ing that neuronal signallsuggest-ing is intimately involved in bone homeostasis, mainly through the leptin-dependent central control of bone formation via the sympathetic system (Batista et al., 2012).
Furthermore, falls are common in persons with MS and are related to physical disability and reduce the quality of life. As stated previously, the prevalence of epilepsy in MS patients is greater than in healthy controls. Epilepsy is also a significant risk factor of falls and fractures. These facts explain a high frequency of fractures in MS patients. Interestingly, smoking is considered to be a major prevent-able risk factor of multiple sclerosis and significant (includ-ed in Fracture Risk Assessment Tool) risk factor of osteo-porosis. It has been indicated that continued smoking is associated with an acceleration in time to secondary pro-gressive MS and that those who quit fare better (Ramanu-jam et al., 2015).
OSTEOPOROSIS TREATMENT OPTIONS
IN MULTIPLE SCLEROSIS
As mentioned in the second paragraph, osteoporosis and fractures definitely worsen the quality of life and are a major cause of morbidity in patients suffering from MS. Unfortunately, no uniform guidelines on such topic have been set so far (Gupta et al., 2014). Therefore, clinicians have to treat patients according to general guidelines on osteoporosis therapy, individual publications as well as their own clinical experience. Drawing any firm conclu-sions from single studies is very difficult due to the fact that these typically include relatively small numbers of participants, have a variety of selection criteria, and in-volve a range of analyses.
Vitamin D and calcium supplementation seems to be a very promising treatment and preventing option. It has been stat-ed that several quantifiable variables of vitamin D recep-tor are associated with MS, which suggests a possible clin-ical immunomodulatory application of vitamin D for MS patients (Al-Temaimi et al., 2015). The significant role of vitamin D in pathological processes occurring in CNS has been documented by other authors as well (Gu et al., 2015).
An anti-inflammatory effect of vitamin D is unclear. It has been showed that high-dose oral vitamin D3 supplemen-tation in patients with the relapsing-remitting MS promi-nently increases serum 25-OHD levels without affecting the markers of systemic inflammation (Røsjø et al., 2015). It can be concluded that future research is definitely needed in this field in order to establish helpful recommendations. Due to this fact, these days clinicians have to follow general rec-ommendations for osteoporosis treatment like guidelines of The UK National Institute for Health and Care Excellence (NICE) or National Osteoporosis Society (NOS) (Aspray
et al., 2014; Gupta et al., 2014; Kmietowicz, 2008). Clinical
evaluation in all patients with MS should include the assess-ment of clinical risk factors of osteoporosis and fractures. First of all, non-pharmacological methods (smoking cessa-tion, reducing alcohol intake, an increased physical activi-ty) are needed. Clinicians and patients should also consider the resistance training which helps to increase bone strength and muscle power as well as reduces the risk of falling as it improves keeping the balance. Furthermore, optimizing vi-tamin D levels and calcium supplementation are essential to maintain the health of bones and their physiological struc-ture (Ishimi, 2015). Where rapid correction of vitamin D deficiency is required (cases of symptomatic bone diseases), it should be given at doses of 800–2000 IU daily (occasion-ally up to 4,000 IU daily), but higher doses might also be needed (Aspray et al., 2014). Vitamin D deficiency should also be corrected by encouraging patients to obtain enough sunlight exposure and by prescribing vitamin D at a dose of 600 IU/day for those aged <70 years and 800 IU/day for those aged >70 years until serum 25-OHD levels reach at least 50 nmol/L. Gupta et al. (2014) also state in their re-view article that even higher intake of up to 4,000 IU, with repeated testing of vitamin D levels to reach 30–40 ng/mL, is suggested by recent recommendations specific for MS pa-tients. Gibson and Summers (2011) suggest that people with an EDSS ≥6 and those who are housebound should have se-rum 25-OHD status determined and, if necessary, treated with a target 25-OHD level of at least 50 nmol/L. The au-thors of the recently published Global Consensus Recom-mendations on Prevention and Management of Nutrition-al Rickets define 25-OHD sufficiency as its serum level >50 mmol/L, insufficiency as 30–50 mmol/L and deficien-cy as <30 mmol/L. In their opinion, for the prevention of rickets and osteomalacia, all children beyond 12 months of age and adults need to meet their nutritional requirements for vitamin D through diet and/or supplementation, which is at least 600 IU/day (15 μg), as recommended by the In-stitute of Medicine (IOM). For the treatment of nutrition-al rickets, the minimnutrition-al recommended dose of vitamin D is 2,000 IU/day (50 μg) for a minimum of 3 months (Munns
et al., 2016). The sufficient calcium intake is 800 mg daily in
children aged between 1 and 10 years old, 1000–1200 mg in youth and adults, 1200–1300 mg in pregnant women, dur-ing lactation, after menopause and in the elderly (Głuszko and Tłustochowicz, 2013). Certainly, treatment with
19
bisphosphonates and other drugs is a very effectiveinter-vention in osteoporosis. Due to this fact, there are detailed recommendations concerning these therapeutic methods (Aspray et al., 2014; Kmietowicz, 2008). However, it is not the topic of our article, thus it will not be discussed herein. Although, there are no official recommendations on the treatment of osteoporosis in MS patients, one can find pub-lications where authors propose their own algorithms for the management of bone health in MS patients (Gupta
et al., 2014).
DISCUSSION AND CONCLUSIONS
It is certain that unified guidelines on the management of osteoporosis in patients suffering from multiple sclerosis are needed. Thanks to a mounting number of different conclu-sions provided in recent publications, we can hope that es-tablishing such recommendations will occur in the nearest future. However, these days clinicians have to follow the re-sults and conclusions of only single studies, often based on small populations. They should focus not only on the treat-ment of osteoporosis in patients with multiple sclerosis, but also on predicting, diagnosing and preventing from osteo-porosis in this group of patients. The most popular and use-ful tool for fracture prediction is Fracture Risk Assessment Tool (FRAX® tool). It can be used as an initial and rough method for estimation and monitoring the risk of osteo-porosis in MS patients. However, it does not take into ac-count a number of secondary causes for osteoporosis that an individual patient has, which arguably limits its useful-ness in MS. Apart from the FRAX® calculator, other pref-erential marker of fracture risk is Dual Energy X-ray Ab-sorptiometry (DXA). People with MS should have BMD measurements performed within a couple of years following the diagnosis identifying a reduced BMD. In addition, those with frequent relapses and/or rapidly progressive disabil-ity should be offered repeated DXA screening because of a higher risk of reduced BMD associated with immobility. No evidence provides guidelines as to the frequency of re-peated DXA scanning in people with MS, although the fre-quency of three to five years has been suggested (Kampman
et al., 2011). There is a strong need to spread the knowledge
on this issue through clinicians by organising topical con-ferences and lectures. It would probably contribute to a bet-ter management of these patients.
In conclusion, the relationship between multiple sclerosis and osteoporosis is a significant clinical problem which re-mains not commonly known and widely discussed among clinicians. Fortunately, many authors are conducting valu-able research projects, publishing helpful results and con-clusions as well as creating large, comprehensive meta-analyses. Thanks to them our knowledge on this interesting issue is still growing. In our article we aimed at presenting and summarising the most important clinical aspects of the relationship between these two diseases. We hope that cli-nicians will find it valuable and helpful in their practice.
Conflict of interest
The authors report no conflict of interest relevant to the manuscript.
References
Al-Temaimi RA, Al-Enezi A, Al-Serri A et al.: The association of vita-min D receptor polymorphisms with multiple sclerosis in a case-control study from Kuwait. PLoS One 2015; 10: e0142265. Aspray TJ, Bowring C, Fraser W et al.; National Osteoporosis Society:
National Osteoporosis Society vitamin D guideline summary. Age Ageing 2014; 43: 592–595.
Batista S, Teter B, Sequeira K et al.: Cognitive impairment is associat-ed with rassociat-educassociat-ed bone mass in multiple sclerosis. Mult Scler 2012; 18: 1459–1465.
Cosman F, Nieves J, Komar L et al.: Fracture history and bone loss in patients with MS. Neurology 1998; 51: 1161–1165.
Dovio A, Perazzolo L, Osella G et al.: Immediate fall of bone forma-tion and transient increase of bone resorpforma-tion in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis. J Clin Endocrinol Metab 2004; 89: 4923–4928.
Gibson JC, Summers GD: Bone health in multiple sclerosis. Osteopo-ros Int 2011; 22: 2935–2949.
Głuszko P, Tłustochowicz W: Osteoporoza. In: Gajewski P, Szcze-klik A (eds.): Interna Szczeklika 2013. 5th ed., Medycyna
Praktycz-na, Kraków 2013: 1938–1943.
Gu SG, Wang CJ, Zhao G et al.: Role of vitamin D in regulating the neural stem cells of mouse model with multiple sclerosis. Eur Rev Med Pharmacol Sci 2015; 19: 4004–4011.
Guenter W, Jabłońska J, Bieliński M et al.: Neuroimaging and genetic correlates of cognitive dysfunction in multiple sclerosis. Psychiatr Pol 2015; 49: 897–910.
Gupta S, Ahsan I, Mahfooz N et al.: Osteoporosis and multiple sclero-sis: risk factors, pathophysiology, and therapeutic interventions. CNS Drugs 2014; 28: 731–742.
Hearn AP, Silber E: Osteoporosis in multiple sclerosis. Mult Scler 2010; 16: 1031–1043.
Hollenbach JA, Oksenberg JR: The immunogenetics of multiple scle-rosis: a comprehensive review. J Autoimmun 2015; 64: 13–25. Ishii M, Egen JG, Klauschen F et al.: Sphingosine-1-phosphate
mobi-lizes osteoclast precursors and regulates bone homeostasis. Nature 2009; 458: 524–528.
Ishimi Y: Osteoporosis and lifestyle. J Nutr Sci Vitaminol (Tokyo) 2015; 61 Suppl: S139–S141.
Kampman MT, Eriksen EF, Holmøy T: Multiple sclerosis, a cause of secondary osteoporosis? What is the evidence and what are the clinical implications? Acta Neurol Scand Suppl 2011: 44–49. Kmietowicz Z: NICE publishes osteoporosis guidance after more than
six years of consultation. BMJ 2008; 337: a2397.
Lambrinoudaki I, Patikas E, Kaparos G et al.: Vitamin D receptor Bsm1 polymorphism, calcium metabolism and bone mineral den-sity in patients with multiple sclerosis: a pilot study. Neurol Sci 2013; 34: 1433–1439.
Marrie RA, Cutter G, Tyry T et al.: A cross-sectional study of bone health in multiple sclerosis. Neurology 2009; 73: 1394–1398. McLean RR: Proinflammatory cytokines and osteoporosis. Curr
Osteoporos Rep 2009; 7: 134–139.
van der Mei IA, Ponsonby AL, Dwyer T et al.: Vitamin D levels in peo-ple with multipeo-ple sclerosis and community controls in Tasmania, Australia. J Neurol 2007; 254: 581–590.
Munns CF, Shaw N, Kiely M et al.: Global Consensus Recommenda-tions on Prevention and Management of Nutritional Rickets. Horm Res Paediatr 2016; 85: 83–106.
Muris AH, Rolf L, Broen K et al.: A low vitamin D status at diagnosis is associated with an early conversion to secondary progressive multiple sclerosis. J Steroid Biochem Mol Biol 2015. DOI: 10.1016/j.jsbmb.2015.11.009.
20
Niino M, Miyazaki Y, Fukazawa T et al.: Vitamin D and latitude as environmental factors in multiple sclerosis. Nihon Rinsho 2014; 72: 1924–1929.
Polachini CR, Spanevello RM, Zanini D et al.: Evaluation of delta-ami-nolevulinic dehydratase activity, oxidative stress biomarkers, and vitamin D levels in patients with multiple sclerosis. Neurotox Res 2016; 29: 230–242.
Ramanujam R, Hedström AK, Manouchehrinia A et al.: Effect of smoking cessation on multiple sclerosis prognosis. JAMA Neurol 2015; 72: 1117–1123.
Røsjø E, Steffensen LH, Jørgensen L et al.: Vitamin D supplementation and systemic inflammation in relapsing-remitting multiple sclero-sis. J Neurol 2015; 262: 2713–2721.
Triantafyllou N, Lambrinoudaki I, Thoda P et al.: Lack of association between vitamin D levels and bone mineral density in patients with multiple sclerosis. J Neurol Sci 2012; 313: 137–141.
Veldman CM, Cantorna MT, DeLuca HF: Expression of 1,25-dihy-droxyvitamin D3 receptor in the immune system. Arch Biochem
Biophys 2000; 374: 334–338.
Weinstock-Guttman B, Gallagher E, Baier M et al.: Risk of bone loss in men with multiple sclerosis. Mult Scler 2004; 10: 170–175. Wolski H, Drwęska-Matelska N, Seremak-Mrozikiewicz A et al.:
[The role of Wnt/β-catenin pathway and LRP5 protein in metab-olism of bone tissue and osteoporosis etiology]. Ginekol Pol 2015; 86: 311–314.
Zorzon M, Zivadinov R, Locatelli L et al.: Long-term effects of intra-venous high dose methylprednisolone pulses on bone mineral density in patients with multiple sclerosis. Eur J Neurol 2005; 12: 550–556.
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